Dr. Grossbard pointed out that, in Europe,
rituximab (Rituxan) has been tested in large numbers of patients with
aggressive non-Hodgkins lymphoma, patients who would ordinarily
have been treated with chemotherapy, and some who relapsed after
chemotherapyand there was marked shrinkage of their tumors.
Though the results do not make rituximab an established therapy
in aggressive disease, Dr. Grossbard said, it gives us a
very good clue to its activity in that class of disease. There
are now a number of ongoing clinical trials of rituximab for the
treatment of aggressive lymphomas in the United States, he said.
Though antibodies are targeted they are not without side effects, he
added; they can cause fever, chills, and occasionally serious
allergic reactions, but generally are well tolerated even in patients
who have had extensive prior treatment of their lymphoma.
Antibodies that carry chemotherapy or radiation directly to the tumor
cells are also being tested. Bexxariodine I-131
tositumomabis a radioactive iodine conjugate of the same type
of antibody used in rituximab and also targets B-lymphoma cells.
Trials using Bexxar, which had mostly been tested in patients with
low-grade lymphoma, are now being expanded to include patients with
aggressive lymphomas. Results so far are good and show relatively
long lasting responses, Dr. Grossbard said.
These antibodies have the advantage of not only targeting the tumor
cell to which they bind, but also irradiating the cells surrounding
the tumor cell. However, people with extensive marrow disease are not
good candidates for this treatment and may have significant toxicity
with this agent, Dr. Grossbard pointed out.
LYM1 (Oncolym) is another antibody conjugate and is attached to
iodine. It is being widely tested in patients with aggressive
non-Hodgkins lymphoma. Significant numbers of patients have
shown good responses, he said.
So in terms of the antibody area, we really are beginning to
see a lot of these therapies taken out of the laboratory and brought
to fruition, Dr. Grossbard said. Were beginning to
see very good activity in patients. What were still learning is
how to properly dose these drugs, how to sequence them with
chemotherapy, and how to give them at the best timeshould they
be given early in the course of disease or later?
The study of potential lymphoma vaccines has been more limited, he
said. They have been studied mostly in patients with low-grade
lymphomas and used to immunize patients who have already achieved
remission after therapy. A portion of the tumor is taken out and
prepared ahead of time to make the vaccine.
There have been intriguing responses that suggest that tumor
recurrences can be delayed in some patients with adequate use of
these vaccines, Dr. Grossbard said, but this is still
highly investigational. We dont know how beneficial this will
be down the road, but it gets us pointing away from the usual
standard doses of chemotherapy and more toward harnessing the immune
system to treat these cancers. I think in the next several years we
will learn how to use these treatments optimally, how to sequence
them for our patients, how to get better and more lasting responses&ldots;
Dr. Chabner took up the question of chemotherapy. The most important
innovation there, he said, has been the use of etoposide, which can
either be added to the standard combination, CHOP (cyclophosphamide,
doxorubicin HCl, Oncovin, and prednisone), or used in an infusional regimen.
The reason for the infusional regimen is that theres some
evidence that by prolonging drug exposure one can overcome drug
resistance. There have been some very interesting trials done at the
National Cancer Institute showing that, in patients who relapse after
remission with CHOP, infusional chemotherapy can produce a reasonably
high rate of responses and some long-term survivors, said Dr.
Chabner. New agents such as topotecan (Hycamtin) are also being
used in conjunction with bone marrow transplantation, he said.
Bone marrow transplantation much earlier in the disease course is
also being studied, he said, and is being used as up-front
treatment in patients with intermediate and high-grade lymphomas who
have bad prognostic factors when they present with their
disease, Dr. Chabner said. It is being compared to conventional
CHOP chemotherapy to see if the cure rate might be higher using
transplantation with high-dose chemotherapy from the start.
One of the more interesting new observations in regard to the use of
antibodies for lymphoma is that, when used with chemotherapy, the
antibodies enhance the response to chemotherapy. Theres a
lot of precedent for this from other studies, such as in breast
cancer using the antibody Herceptin with chemotherapy, Dr.
Chabner said. There is the potential to do the same with
lymphoma patients. The logical next step is to combine rituximab with
chemotherapy, and in fact several protocols are now testing this
approach. Weve participated in one such study here at
Masachusetts General Hospital and there was a very high up front
response rate to the combination. However, the study is still ongoing
and preliminary, so were not sure if its really better
than CHOP alone. The regimen needs to be confirmed in a larger
trial, he added.
Currently, we are conducting a trial of rituximab with
infusional chemotherapy, a regimen that has been piloted at the
National Cancer Institute and has shown good activity in relapsed
patients, Dr. Chabner said. So there is some hope that
the combination of rituximab with chemotherapy will be advantageous.